1. Field of the Invention
The present invention relates to a pharmaceutical composition containing a biologically active polypeptide suitable for oral administration. More particularly, the present invention relates to a pharmaceutical composition for oral administration containing one of LHRH, an LHRH analog, somatostatin and a somatostatin analog. In another aspect, the present invention relates to a process for rendering the biologically active polypeptide suitable for oral administration.
2. Description of Related References
M. Kidron et al., U.S. Pat. No. 4,579,730 (Apr. 1, 1986), disclose a pharmaceutical composition for the oral administration of insulin comprising insulin, a bile acid or alkali metal salt thereof to promote absorption of insulin, a protease inhibitor to protect insulin against proteolysis, and the use of enterocoating of the above active mixture.
M. Saffran et al., Science, Vol. 233, 1281 (1986), describe that the oral administration of polypeptide drugs has been well known to be precluded by their digestion in the stomach and small intestine. These authors further describe that peptide drugs can be protected against attack by digestive enzymes by coating the drug with an impermeable polymer film wherein the coating polymer is not susceptible to the action of digestive enzymes. The ability of microflora to reductively cleave azoaromatic bonds has been known. Thus, azoaromatic polymer coated capsules and pellets of vasopressin or insulin were used to determine whether the azoaromatic polymer could be used for the oral delivery of peptide drugs. Vasopressin and insulin were found to be absorbed after administration of the capsules by depositing the capsules in the stomach of rats. Further, oral administration to rats of vasopressin and insulin protected with azoaromatic polymer coatings produced biological responses characteristic of the peptide hormones. These results were taken to show that the azoaromatic polymer delivery system operates in principle.
E. German Patent Application No. DD 252 539 A published Dec. 23, 1987, Derwent Abstract 88-133631/20, discloses oral administration of active peptides such as insulin, Substance P, GnRH or its analogs, atrial natriuretic peptide, a synthetic thymus peptide, an ACE- or renin-inhibiting peptide or a neuropeptide in the form of controlled-release compositions comprising the active peptide immobilized on a carrier, a gastrointestinal absorption promoter, and a protease inhibitor. The absorption promoter is a protein/fatty acid condensate and the protease inhibitor is epsilon-aminocaproic acid or derivative thereof or aprotinin.
European Patent Application No. EP 177,342 A published Sep. 4, 1986, Derwent Abstract 86-095678/15, discloses oral therapeutic protein formulations with enhanced absorption comprising as active ingredient an amphilipophilic protein of molecular weight over 12,000, a lipophilic water-immiscible compatible vehicle usable in enteric formulations, and a gastrointestinal tract absorption enhancing agent. Described as particularly suitable for administration as active ingredient are human growth hormone, human alpha- or gamma-interferon, human tissue plasminogen activator, human tumor necrosis factor, bovine growth hormone or alpha- or gamma-interferon, porcine growth hormone, chicken growth hormone, or structurally similar bioactive equivalents of the above. Mineral oil is mentioned as the preferred lipophilic vehicle. There is mentioned as the gastrointestinal tract absorption enhancing agent hydoxyaryl or hydroxylalkylaryl acids and their salts, esters or amides, or enamine derivatives of 1,3-dicarbonyl compounds and aminoacids and their salts, amides or esters. Suitable vehicles include triglycerides, esterified glycols, polyglycols with hydrophobic alkyl side chains, phospholipids, sterols and especially mineral oil. As the absorption enhancer, there is mentioned that an agent having Ca chelating properties may also be present. A preferred absorption enhancer is sodium salicylate.
European Patent Application No. EP 111,841 A published Jun. 27, 1984, Derwent Abstract 84-159888/26, discloses nasal compositions comprising a nona- or deca-peptide or its salts having LHRH agonist or antagonist activity together with a bile acid or its salt as a surfactant in aqueous solution, the composition having greatly enhanced absorption across the nasal membrane. Representative of the LHRH analog is the compound represented by the formula EQU (pyro)Glu-His-Trp-Ser-Tyr-3-(2-naphthyl)-D-Ala-Leu-Arg-Pro-Gly-NH.sub.2.
Sodium glycocholate was used as the surfactant, together with buffer.
M. V. Nekola et al., Science, Vol. 218, 160 (1982) disclose suppression of ovulation in the rat by an orally active antagonist of luteinizing hormone-releasing hormone. The active compound was given by gavage on the afternoon of proestrus and ovulation was delayed for at least one day in all animals given 2 mg of antagonist and oral administration of the same also blocked preovulatory surge of luteinizing hormone.
H. Okada et al., J. Pharm. Sci., 71(12), 1367 (1982), evaluate the absorption of a potent luteinizing hormone-releasing hormone analog, leuprolide, through different routes such as, for example, vaginal, rectal, nasal, and oral administration, in rats. For oral administration, a mixed micellar solution with monoolein, sodium taurocholate, and sodium glycocholate was prepared. Vaginal administration showed the greatest potency among nonparenteral routes followed successively by rectal, nasal and oral administration.
N. Yokoo et al., Yakugaku Zasshi, 108. (2), 164-169 (1988) and S. Fujii et al., J. Pharm. Pharmacol., 37, 545-549 (1984), disclose the use of the chymotrypsin inhibitor, 4-(4-isopropylpiperazinocarbonyl)phenyl 1,2,3,4-tetrahydro-1-naphthoate methanesulfonate (FK-448) in the promoting effect on the intestinal absorption of insulin based on the inhibition of proteolytic enzymes.
E. Ziv et al., Life Sciences, 29 (8), 803-809 (1981) and E. Ziv et al., Biochemical Pharmacology, 36 (7), 1035-1039 (1987), disclose the absorption of insulin mixed with sodium deoxycholate or sodium cholate from the rectal mucosa of diabetic and non-diabetic rats.
Biologically active, that is, hormonally active, polypeptides comprise a diverse group of polypeptides. Because of their functional specificity, they can be conveniently grouped into discrete classifications on the basis of physiological effect. For example, LHRH and analogs thereof act on the anterior pituitary gland to effect release of hormones which affect the activity of reproductive organs. Somatostatin analogs block secretion of growth hormone from the pituitary gland, secretion of gastric acid and pepsin from the stomach lining, and release of both glucagon and insulin from the pancreatic islets. Somatostatin also acts to inhibit the absorption of glucose, amino acids and fat from the gastrointestinal (GI) tract as well as to inhibit GI motility.
LHRH analogs and somatostatin analogs are relatively short acting in the body. Thus, attempts have been made to modify the compounds to obtain compounds that are longer acting and more potent.
LHRH analogs include compounds having agonist or antagonist effects. Representative, known LHRH agonists include those compounds that are disclosed in Nestor et al., U.S. Pat. No. 4,234,571 (Nov. 18, 1980). Representative, known LHRH antagonists include those compounds disclosed in Nestor et al., U.S. Pat. No. 4,801,577 (Jan. 31, 1989).
Other representative LHRH analogs include those nona- or decapeptides having LHRH agonist or antagonist activity disclosed, along with processes for preparation thereof, in the following U.S. Pat. Nos. 3,813,382; 3,843,065; 3,849,389; 3,855,199; 3,886,135; 3,890,437; 3,892,723; 3,896,104; 3,901,872; 3,914,412; 3,915,947, 3,929,759; 3,937,695; 3,953,416; 3,974,135; 4,010,125, 4,018,914, 4,022,759; 4,022,760; 4,022,761; 4,024,248; 4,034,082; 4,072,668; 4,075,189; 4,075,192; 4,086,219; 4,101,538; 4,124,577; 4,124,578, 4,143,133; 4,234,571, 4,253,997; 4,292,313; 4,341,767.
Representative, known somatostatin analogs include those described in the following references: U.S. Pat. Nos. 4,728,638; 4,342,671; 4,310,518; and 4,291,022; European Patents No. 0,022,578 and 0,175,644; Proc. Natl. Acad. Sci. USA, 83, 1896(1986); Life Sciences. 31, 1133(1982); Life Sciences, 41, 1011(1987); Proc. Natl. Acad. Sci. USA. 80, 1078(1983); and Life Sciences. 40, 419(1987).